The major mechanism for biological degradation of neuropeptides in the human lung is believed to depend on the epithelial enzyme neutral endopeptidase (NEP). Diminished activity of this enzyme correlates with potentiation of the effects of the neuropeptide tachykinins Substance P and Substance K (neurokinin A). This group hypothesizes that changes in the NEP gene expression, messenger RNA processing, and enzyme activity underlie many features of chronic lung disease. In order to provide data linking NEP and chronic lung disease, they will complete the molecular cloning of the cDNA for this enzyme from human lung and establish the structure of the splice variants. The cloned isoforms will be expressed in cultured cells in order to correlate structure with function. The structural data will enable the design of synthetic oligonucleotide probes for polymerase chain reaction (PCR), which will be used to examine the presence of NEP isoform expression in pathologic tissues, as well as bronchoalveolar lavaged cells from epidemiologically defined subjects with characterized pulmonary function. The role of inflammation in NEP gene expression will be determined in cell culture and SO2-treated experimental animals to explore the hypothesis that inflammation, through activation of protein kinase C, leads to the down-regulation of the NEP gene and consequent neuropeptide potentiation in chronic lung disease.